Levetiracetam (levebel) Versus Carbamazepine Monotherapy for Focal Epilepsy in Children: A randomized clinical trial.

Objective: This study aimed at comparing the effect of a newly approved drug leveitiracetam (LEV) versus carbamazepine (CBZ) in the treatment of childhood focal epilepsy. Methods & Materials The study population included newly diagnosed children with focal epilepsy (1-16 years old) referring to the Pediatric Neurology Ward of Quaem Hospital, Mashhad, Iran from May 2013 to March 2014. The subjects were randomly treated with LEV or CBZ. Patients were followed for seizure control and drug side effects throughout six months. We assessed liver function and complete blood count for all patients through one month and they were asked about significant side effects, such as drowsiness، restlessness, and skin reaction. Eventually, they were assigned in two groups (n=25) receiving LEV and CBZ. Results In our study, two cases in the LEV group were excluded because of severe agitation. Relapsing seizures were observed in 3 (13%) and 10 (40%) patients in LEV and CBZ groups, respectively. The seizure was not repeated in 15 cases (60%) in the CBZ group and 20 cases (87%) in the LEV group. The results of the Chi-squared test showed significant differences in the responses to treatment between the groups (P=0.03). Agitation was the most prevalent complication in the LEV group, whereas drowsiness was more common in the CBZ group. Fortunately, liver enzyme dysfunction and blood cell disturbances were not observed in the subjects. Conclusion According to the findings, there were significant differences in controlling seizures between two groups that indicated the effectiveness of LEV (87%) in the suppression of focal seizure.


Introduction
Epilepsy is a demanding neurological condition that affects many people worldwide. Selecting an appropriate antiepileptic drug (AED) is still challenging, because the selected drug should be effective, safe, and tolerable. Older generation of AEDs, such as phenobarbital and phenytoin are not widely accepted as a primary monotherapy and also long-term therapy for focal seizures, because of their side effects (1). This problem is more common in pediatrics, particularly those over the age of one year. Only topiramate and oxcarbazepine are approved as monotherapy despite their side effects, such as leukopenia, aplastic anemia and drug-induced hepatitis. Because these drugs have the potential for drug interactions, reducing the serum level of other AEDs, and producing drug -drug interaction, it is important to consider the safety and efficacy of an AED separately for monotherapy and adjunctive therapy (2).
The newer generation of AEDs have often more favorable side effects, including lesser somnolence and blood dyscrasia than the traditional AEDs.
However, no comparative study has demonstrated the improved efficacy over carbamazepine (CBZ), phenytoin or valproic acid (3).
Levetiracetam (LEV), the S-enantiomer of alphaethyl-2-oxo-1-pyrrolidine acetamide, is a novel AED that has been approved for use as an addon therapy for partial-onset seizures in children older than one year. In addition, LEV may provide effective seizure control when used as monotherapy (4). No serious toxicity has been reported for LEV (5). LEV does not affect the liver enzymes, like CYP450. Hence, there is no report on its major interaction with other AEDs (2).
Little evidence is available for LEV monotherapy in children younger than 16 years (6). Although several other studies have demonstrated successful conversion to monotherapy in a small number of children, the response rate with various durations of treatment in children with refractory epilepsy was as high as 66% (7,8).
To date, there are limited comparative findings regarding older and newer generations of AEDs (9) and there is no prospective study for this comparison. This study aimed at comparing the effects of LEV and CBZ as monotherapy in children with focal seizures.  These groups were then sub-divided into two groups: responsive and non-responsive to therapy.

Materials & Methods
Patients who completed the trial were considered to receive the allocated treatment until data analysis.

Statistics
Due to the lack of relevant study, this study was done as a pilot research. The subjects were initially dichotomized into two groups: those who treated with LEV and those with CBZ. The Student t-test and Chi-square test were used to compare continuous parametric and nonparametric data, respectively. The Fisher's exact test was used for categorical variables. The seizure-free period was calculated for each subject. The occurrence of adverse events was compared between the two treatment groups using the dosage at the onset of the adverse events and the interval between the initiation of the AED administration and the occurrence of the adverse events.

Results
The initial evaluation sowed 25 patients with seizures who were younger than 16 years treated with LEV and 25 cases treated with CBZ who met inclusion criteria. The demographic characteristics of the two treatment groups were comparable and all patients were followed for 6 months after the initiation of monotherapy ( There was no significant difference between the participants who were free of seizure attacks during a six-month follow-up and those who had seizure attacks. Regardless of the seizure type, Chi-squared test revealed a statistically significant difference in the response to the therapy between the CBZ and LEV groups (P value: 0.035).
The participants on LEV monotherapy had a significantly higher response rate. Moreover, in the LEV group, there was no significant difference between the participants who were free of seizure attacks through a six-month follow-up and those who were not.
In the CBZ monotherapy group, five participants  seizure-frequency counts provided by the parents.
In the present study, all participants were subjected to monotherapy for at least six months. The majority of participants (87%) receiving LEV, (20/23 participants) experienced seizure freedom through a six-month follow-up. This proportion was significantly higher than the participants in the CBZ group (60%) who were seizure-free during the follow-up period. A previous study on 18 children treated with LEV did not report information about the conversion, treatment initiation, duration of treatment, and clinical response (12).
Another relevant study reported that 73% of the participants receiving LEV and 65% treated with CBZ were free of seizures. However, the proportion of those treated with CBZ who were free of seizures was slightly higher than our findings (11). Another study reported no statistically significant difference in seizures freedom between participants treated with LEV and CBZ (3). In contrast, our findings revealed a statistically significant difference in seizure remission between the participants in the LEV and CBZ groups (P value: 0.035). Other studies also reported a higher proportion of seizurefree response among participants with partial seizure who received LEV monotherapy (8,9).
Furthermore, 57% of the participants (children younger than 4 years) who were treated with LEV or CBZ monotherapy for focal seizures have been reported to be free of seizures during the first six months of follow-up (13).
We prescribed LEV at an initial dose of 10 mg/kg/d that was increased to 30 mg/kg/d and continued.
Another study also suggested a lower dose of LEV (≤30 mg/kg/d). Ben-Menachem et al. reported that changing the LEV therapy from adjunctive therapy to monotherapy at a dose of 1500mg twice a day was effective in reducing or ceasing the seizures attack (15).

Studies on LEV monotherapy in adults and children
have reported the effectiveness at relatively lower doses of LEV (12,13).
These studies also suggested LEV as an effective medication for seizure remission in childhood focal epilepsy. Among the patients treated with LEV (12,13,15), there were no significant differences in seizure type. Both CBZ and LEV were well tolerated as an initial monotherapy (12,13). effect was also found between the two groups (P value: 0.012), which is consistent with the findings of other studies (16)(17)(18)(19)(20).
It is recommended to conduct more studies using a larger sample size to compare the presence of intolerable side effects more accurately between the two groups receiving the specified monotherapies.
It can provide an appropriate finding regarding the effectiveness of a specific therapy more specifically . Our study indicated a significant difference in the effectiveness of the LEV as the first-line medication compared with the CBZ. This implies the noninferiority to CBZ and a more favorable effectiveness of the LEV as a monotherapy for focal seizures. However, data analysis showed no statistically significant difference between the two groups.
To select a treatment for a patient with newly diagnosed epilepsy, the side effects and long-term safety should be considered. LEV can probably be a proper substitution for CBZ because it is associated with lower side effects, more safety, tolerability, and simpler pharmacokinetics that makes it a promising AED to be used as initial monotherapy in newly diagnosed epilepsy cases.
The current study showed that children with newly diagnosed focal epilepsy treated with LEV had a better positive prognosis than those receiving CBZ.

Strengths and Limitations
The use of seizures remission as an ultimate goal of treatment and as a marker of efficacy, the relative homogeneity between the groups, and using prospective design (randomized controlled trials) were the strengths of this study. However, this study was a pilot study using a small sample size. Hence, the direct comparison between the two groups with the antiepileptic monotherapies was limited. This study can provide strong findings for future trials on LEV monotherapy with a larger sample size in children younger than 16 years with focal epilepsy.

In conclusion
To select a treatment for a patient with newly diagnosed epilepsy, the side effects and long-term safety should be considered. LEV can probably be a proper substitution for CBZ because it is associated with lower side effects, more safety, tolerability, and simpler pharmacokinetics that makes it a promising AED to be used as initial monotherapy in newly diagnosed epilepsy cases.
The current study showed that children with newly diagnosed focal epilepsy treated with LEV had a better positive prognosis than those receiving CBZ.
The use of seizures remission as an ultimate goal of treatment and as a marker of efficacy, the relative homogeneity between the groups, and using prospective design (randomized controlled trials) were the strengths of this study. However, this study was a pilot study using a small sample size. Hence, the direct comparison between the two groups with the antiepileptic monotherapies was limited. This study can provide strong findings for future trials on LEV monotherapy with a larger sample size in children younger than 16 years with focal epilepsy